This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
The potential utilities of selective cyclooxygenase-2 inhibitors are discussed in the following articles:
1. John Vane, "Towards a better aspirin" in Nature, Vol. 367, pp. 215-216, 1994. PA0 2. Bruno Battistini, Regina Botting and Y. S. Bakhle, "COX-1 and COX-2: Toward the Development of More Selective NSAIDs" in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994. PA0 3. David B. Reitz and Karen Seibert, "Selective Cyclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995. PA0 4. Don E. Griswold and Jerry L. Adams, "Constituative Cyclooxygenase (COX-1) and Inducible Cyclooxygenase (COX-2): Rationale for Selective Inhibition and Progress to Date" in Medicinal Research Reviews, Vol. 16, pp. 181-206, 1996. PA0 3-(4-Methylsulfonyl)phenyl-2-phenyl-5-trifluoromethylpyridine; PA0 2-(3-Chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine; PA0 2-(4-Chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine; PA0 2-(4-Fluorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine; PA0 3-(4-Methylsulfonyl)phenyl-2-(3-pyridinyl)-5-trifluoromethylpyridine; PA0 5-Methyl-3-(4-methylsulfonyl)phenyl-2-phenylpyridine; PA0 2-(4-Chlorophenyl)-5-methyl-3-(4-methylsulfonyl) phenylpyridine; PA0 5-Methyl-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine; PA0 5-Chloro-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl) pyridine; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(4-pyridinyl) pyridine; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; PA0 2-(4-Chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic acid methyl ester; PA0 2-(4-Chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic acid; PA0 5-Cyano-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine hydromethanesulfonate; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine hydrochloride; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine Hydrochloride; PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine; and PA0 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine hydromethanesulfonate. PA0 AA=arachidonic acid PA0 Ac=acetyl PA0 AIBN=2.2.sup.- -azobisisobutyronitrile PA0 BHT=butylated hydroxytoluene PA0 Bn=benzyl PA0 CSA=camphor sulfonic acid (racemic) PA0 dba=dibenzylideneacetone PA0 DMAP=4-(dimethylamino)pyridine PA0 DMF=N,N-dimethylformamide PA0 DMSO=dimethyl sulfoxide PA0 EDTA=ethylenediaminetetraacetic acid PA0 ESA=ethane sulfonic acid PA0 Et.sub.3 N=triethylamine PA0 HBSS=Hanks balanced salt solution PA0 HEPES=N-[2-Hydroxyethyl]piperazine-N.sup.1 -[2-ethanesulfonic acid] PA0 HWB=human whole blood PA0 KHMDS=potassium hexamethyldisilazane PA0 LDA=lithium diisopropylamide PA0 LPS=lipopolysaccharide PA0 mCPBA=m-chloroperbenzoic acid PA0 MMPP=magnesium monoperoxyphthalate PA0 Ms=methanesulfonyl=mesyl PA0 Ms0=methanesulfonate=mesylate PA0 MTBE=methyl tert-butyl ether PA0 NBS=N-bromosuccinimide PA0 NCS=N-chlorosuccinimide PA0 NIS=N-iodosuccinimide PA0 NMO=N-methylmorpholine-N-oxide PA0 NMP=N-methylpyrrolidone PA0 NSAID=non-steroidal anti-inflammatory drug PA0 oxone.RTM.=2KHSO.sub.5.KHSO.sub.4.K.sub.2 SO.sub.4 PA0 PCC=pyridinium chlorochromate PA0 PDC=pyridinium dichromate PA0 PEG=polyethyleneglycol PA0 Ph=phenyl PA0 pyr=pyridinyl PA0 r.t.=room temperature PA0 rac.=racemic PA0 Tf=trifluoromethanesulfonyl=triflyl PA0 TfO=trifluoromethanesulfonate=triflate PA0 THF=tetrahydrofuran PA0 TLC=thin layer chromatography PA0 Ts=p-toluenesulfonyl=tosyl PA0 TsO=p-toluenesulfonate=tosylate PA0 Tz=1H (or 2H)-tetrazol-5-yl PA0 SO.sub.2 Me=methyl sulfone PA0 SO.sub.2 NH.sub.2 =sulfonamide PA0 Me=methyl PA0 Et=ethyl PA0 n-Pr=normal propyl PA0 i-Pr isopropyl PA0 n-Bu=normal butyl PA0 i-Bu=isobutyl PA0 s-Bu=secondary butyl PA0 t-Bu=tertiary butyl PA0 c-Pr=cyclopropyl PA0 c-Bu=cyclobutyl PA0 c-Pen=cyclopentyl PA0 c-Hex=cyclohexyl PA0 bid=bis in die=twice daily PA0 qid=quater in die=four times a day PA0 tid=ter in die=three times a day
WO 96/10012 (DuPont Merck, Apr. 4, 1996) discloses compounds represented by Formula A as being useful in the treatment of COX-2 mediated diseases, by virtue of their selective inhibition of COX-2 rather than COX-1. We have now discovered that a subset of the compounds represented by A, in which --J--K--L-- is --NCHCH--, X is a bond, R.sup.1 is aromatic and R.sup.3 and R.sup.4 are not both hydrogen show unexpectedly superior selectivity for the inhibition of COX-2 over COX-1 and/or superior potency as compared to the closest species disclosed in 96/10012. This subset of compounds is the subject of the present invention and is represented by Formula I. ##STR2##
Of the over 175 specific compounds disclosed in WO 96/10012, only 4 of them are pyridines, and none of these latter contain a substituent (R.sup.3 or R.sup.4 in A) on the pyridine ring.
WO 96/16934 (Searle, Jun. 6, 1996) discloses compounds represented by structure B as being useful for the treatment of inflammation and related disorders. Chemically, these compounds differ from those of the present invention in that the central of the three aromatic rings is benzene rather than pyridine.